It's complicated: The relationship of non-narcotic medications and postoperative opioid use in radical cystectomy patients.

INTRODUCTION: The effect of individual non-narcotic analgesics in cystectomy enhanced recovery after surgery (ERAS) is unknown. Additionally, many non-narcotic medications are associated with side effects pertinent to the cystectomy population. To better understand the actual use and utility of these medications, we sought to characterize the association between non-narcotic medications and milligram morphine equivalent (MME) narcotic score during the postoperative inpatient stay. METHODS: We reviewed 260 consecutive ERAS cystectomy patients. The MME impact of non-narcotic compliance and cumulative dose of medication received was evaluated separately with general linear models. We also assessed relationship of non-narcotic compliance to patient reported pain score, length of stay (LOS), and time to return of bowel function (ROBF) and performed manual review of postoperative documentation to identify reasons for medication noncompliance. RESULTS: Compliance with postoperative acetaminophen, gabapentin, and ketorolac was low. There was an inverse relationship between ketorolac dose and MME on postoperative day 1 (-0.026 MME/mg; P = 0.004) and postoperative day 2 (-0.33 MME/mg; P < 0.001). Compliance with ketorolac was associated with lower MME on postoperative day 1 (26.1 MME v. 33.6 MME; P = 0.023). There were no such associations identified with gabapentin or acetaminophen. Gabapentin compliance was associated with earlier ROBF (3.7 days v. 4.3 days; P = 0.006). Ketorolac compliance was associated with lower pain score on POD1 (3.25 VAS v. 4.07 VAS; P = 0.019) and POD2 (3.05 VAS v. 3.85 VAS; P = 0.040) There was no association between medication compliance and LOS. The most common reasons identified for non-compliance with gabapentin and ketorolac were renal function concerns (38% and 40% respectively), bleeding concerns with ketorolac (20%) and concerns for neurologic adverse effect with gabapentin (16%). CONCLUSION: Compliance with non-narcotic medications in our ERAS cystectomy protocol was poor. There was a modest association with ketorolac and postoperative MME but no association with gabapentin or acetaminophen. Further study will clarify the role of these medications for cystectomy patients. Component specific analysis of protocolized care is valuable and may alter care pathways.

Persistent opioid and benzodiazepine use after radical cystectomy in enhanced recovery after surgery (ERAS) patients.

OBJECTIVES: Opioid use, misuse, and diversion is of paramount concern in the United States. Radical cystectomy is typically managed with some component of opioid pain control. We evaluated persistent opioid and benzodiazepine use after radical cystectomy and assessed the impact of their preoperative use on this outcome. We also explored associations between preoperative use and perioperative outcomes. METHODS AND MATERIALS: We used prospectively maintained data from our enhanced recovery after surgery (ERAS) cystectomy database and the Prescription Reporting with Immediate Medication Utilization Mapping (PRIMUM) database to identify controlled substance prescriptions for radical cystectomy patients. We separated patients by frequency of preoperative opioid and/or benzodiazepine prescriptions (0, 1, 2+) and used these cohorts to explore persistent use (prescription 3-12 months after surgery) alongside perioperative outcomes. RESULTS: Our cohort included 257 patients undergoing cystectomy at a single institution from 2017 to 2021. Preoperative opioid and benzodiazepine prescriptions were documented for 120 (46.7%) and 26 (10.1%) patients, respectively. Persistent opioid use was observed in 20 (14.6%) of opioid-naive patients (no prescriptions in 9 months prior to surgery) while 13 (19.7%) patients with 1 preoperative prescription and 28 (51.9%) patients with 2 or more preoperative prescriptions demonstrated persistent use. New persistent benzodiazepine use occurred in 6 (2.6%) patients. Overall persistent benzodiazepine use was present in 11 (4.3%) patients. In a multivariable model, preoperative opioid and benzodiazepine prescriptions were associated with persistent opioid use (P < 0.001; P = 0.027 respectively). No association was identified between preoperative opioid or benzodiazepine usage and perioperative outcomes including length of stay, return of bowel function, inpatient opioid usage, inpatient or discharge complications, readmissions, or emergency department visits. Inpatient pain scores were noted to be higher in patients with ≥ 2 preoperative opioid prescriptions (P = 0.037). CONCLUSIONS: Persistent opioid use was present in 23.7% of patients, with a new persistent use rate of 14.6%. Benzodiazepine use was less frequent than opioids, with a small number demonstrating new persistent use. Preoperative opioid and benzodiazepine use is associated with persistent opioid use postoperatively. Preoperative opioid and benzodiazepine use did not affect perioperative outcomes in our cohort.

Impact of dedicated renal enhanced recovery after surgery (RERAS) program on postoperative opioid consumption and evaluation of surgeon-specific compliance to the program.

INTRODUCTION AND OBJECTIVE: Enhanced Recovery After Surgery (ERAS) protocols have been increasingly applied to urologic surgeries such as cystectomy and prostatectomy, though research defining protocols and outcomes for renal ERAS programs (RERAS) for nephrectomy remains limited. We aim to assess perioperative outcomes following implementation of our RERAS protocol modified from ERAS society cystectomy guidelines, as well as describe compliance with protocol guidelines. METHODS: We performed a retrospective cohort analysis of 400 patients who underwent partial or radical nephrectomy between October 2017 and August 2020. RERAS protocol was initiated September 30, 2018, and patients were categorized into pre- and post-RERAS implementation cohorts based on surgery date. Perioperative outcomes including complications, 30-day readmissions, length of stay, and opioid consumption were compared across pre- and post-RERAS cohorts. Protocol compliance was reported based on adherence to program recommendations. RESULTS: Among 400 patients included in analysis, the pre-RERAS cohort included 133 patients and the post-RERAS cohort included 267 patients. There were no differences in overall complications (P = 0.354) and 30-day readmissions (P = 0.078). Length of stay (P < 0.001) and postoperative opioid consumption (P < 0.001) were significantly reduced post-RERAS. We observed an increase in compliance with RERAS recommendations over time (P< 0.001). CONCLUSION: RERAS implementation was associated with decreased length of stay and opioid usage, underscoring the benefits of program adoption in an era of opioid dependence and strained hospital capacity. Successful initiation of a RERAS protocol requires intentional organization and buy in from all providers involved.

Directed evolution reveals the mechanism of HitRS signaling transduction in Bacillus anthracis.

Two component systems (TCSs) are a primary mechanism of signal sensing and response in bacteria. Systematic characterization of an entire TCS could provide a mechanistic understanding of these important signal transduction systems. Here, genetic selections were employed to dissect the molecular basis of signal transduction by the HitRS system that detects cell envelope stress in the pathogen Bacillus anthracis. Numerous point mutations were isolated within HitRS, 17 of which were in a 50-residue HAMP domain. Mutational analysis revealed the importance of hydrophobic interactions within the HAMP domain and highlighted its essentiality in TCS signaling. In addition, these data defined residues critical for activities intrinsic to HitRS, uncovered specific interactions among individual domains and between the two signaling proteins, and revealed that phosphotransfer is the rate-limiting step for signal transduction. Furthermore, this study establishes the use of unbiased genetic selections to study TCS signaling and provides a comprehensive mechanistic understanding of an entire TCS.

Comparison of guideline recommendations for antimicrobial prophylaxis in urologic procedures: variability, lack of consensus, and contradictions.

PURPOSE: This review assesses guideline discrepancies for urologic surgery antimicrobial prophylaxis and identifies opportunities for improvement of antimicrobial prophylaxis and stewardship. METHODS: Literature search using PubMed, Embase, Cochrane, and association websites identified guidelines for review from the American Urological Association, Canadian Urological Association, European Association of Urology, Japanese Urological Association, and Association of Health-System Pharmacists/Infectious Disease Society of America/Surgical Infection Society/Society for Healthcare Epidemiology of America. RESULTS: The greatest variability between guidelines was found in prophylaxis recommendations for prostate brachytherapy, transurethral resection of bladder tumor, extracorporeal shock wave lithotripsy (ESWL), and ureteroscopy with manipulation. Variability was also present in recommended duration of prophylaxis and recommended antibiotic. Contradictions between guidelines existed regarding prophylaxis for patients with indwelling stents undergoing ESWL, as well as for patients at risk of endocarditis undergoing urologic procedures. Procedures with the least variability in prophylaxis recommendation included diagnostic procedures (cystourethroscopy, urodynamic studies, and diagnostic ureteroscopy), transurethral resection of prostate, transrectal prostate biopsy, percutaneous nephrolithotomy, procedures involving prosthesis placement or intestine, and open or laparoscopic procedures. CONCLUSIONS: Consensus recommendations are present for several procedures, many of which still rely on non-urologic data. Several other procedures have variability in recommendations, generally due to a lack of strong data. The use of risk factors as indication for prophylaxis in many procedures is at times ambiguous and confusing. Together, these observations indicate a need for further research to provide more robust and consistent guidelines for antimicrobial prophylaxis and stewardship in the field of urology.

Two-component system cross-regulation integrates Bacillus anthracis response to heme and cell envelope stress.

Two-component signaling systems (TCSs) are one of the mechanisms that bacteria employ to sense and adapt to changes in the environment. A prototypical TCS functions as a phosphorelay from a membrane-bound sensor histidine kinase (HK) to a cytoplasmic response regulator (RR) that controls target gene expression. Despite significant homology in the signaling domains of HKs and RRs, TCSs are thought to typically function as linear systems with little to no cross-talk between non-cognate HK-RR pairs. Here we have identified several cell envelope acting compounds that stimulate a previously uncharacterized Bacillus anthracis TCS. Furthermore, this TCS cross-signals with the heme sensing TCS HssRS; therefore, we have named it HssRS interfacing TCS (HitRS). HssRS reciprocates cross-talk to HitRS, suggesting a link between heme toxicity and cell envelope stress. The signaling between HssRS and HitRS occurs in the parental B. anthracis strain; therefore, we classify HssRS-HitRS interactions as cross-regulation. Cross-talk between HssRS and HitRS occurs at both HK-RR and post-RR signaling junctions. Finally, HitRS also regulates a previously unstudied ABC transporter implicating this transporter in the response to cell envelope stress. This chemical biology approach to probing TCS signaling provides a new model for understanding how bacterial signaling networks are integrated to enable adaptation to complex environments such as those encountered during colonization of the vertebrate host.